Manias, Janet L; Plante, Isabelle ORCID: https://orcid.org/0000-0003-2080-6450; Gong, Xiang-Qun; Shao, Qing; Churko, Jared; Bai, Donglin et Laird, Dale W
(2008).
Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant
Cardiovascular Research
, vol. 80
, nº 3.
pp. 385-395.
DOI: 10.1093/cvr/cvn203.
Résumé
AIMS: More than 40 mutations in the GJA1 gene encoding connexin43 (Cx43) have been linked to oculodentodigital dysplasia (ODDD), a pleiotropic, autosomal dominant disorder. We hypothesized that even with a significant reduction in the levels of Cx43 in a mutant mouse model of ODDD (Gja1(Jrt/+)) harbouring a G60S mutation (Cx43(G60S)), cardiomyocyte function may only be moderately compromised given that a majority of mutant mice typically survive.
METHODS AND RESULTS:Western blotting and quantitative reverse transcriptase-polymerase chain reaction in conjunction with immunofluorescence were used to assess the expression and localization of Cx43 in hearts and cultured cardiomyocytes from wild-type and Gja1(Jrt/+) mice. Dye-coupling and dual whole cell patch-clamp recordings were also used to assess the gap junction channel status in cultured cardiomyocytes from wild-type and mutant mice. Cardiac tissue from adult Gja1(Jrt/+) mice revealed a 60-80% reduction in Cx43 protein with a preferential loss of the highly phosphorylated forms of Cx43. Compensation via the up-regulation of Cx40 or Cx45 was not observed. Immunofluorescent analysis of cultured cardiomyocytes revealed a trafficking defect, with a decrease in Cx43 plaques and a large population of Cx43 being retained in the Golgi apparatus. However, cultured cardiomyocytes from mutant mice remained beating with a 50% decrease in coupling conductance.
CONCLUSION: These results suggest that the Cx43(G60S) mutant impairs normal trafficking and function of co-expressed Cx43 with no dramatic effect on cardiomyocyte function, suggesting that Cx43 is biosynthesized in excess of an essential need.
Type de document: | Article |
---|---|
Mots-clés libres: | Connexin43; Gap junctions; Cardiomyocytes; Mutant mice; Disease |
Centre: | Centre INRS-Institut Armand Frappier |
Date de dépôt: | 02 août 2024 14:11 |
Dernière modification: | 02 août 2024 14:11 |
URI: | https://espace.inrs.ca/id/eprint/14943 |
Gestion Actions (Identification requise)
![]() |
Modifier la notice |